Branched adamantyl and noradamantyl aryl-and aralkylpiperazines with serotonin 5-HT 1A activity

ABSTRACT

This invention provides compounds and methods using them to provide neuroprotection and prevent or limit processes of neurodegeneration in mammals, including Alzheimer&#39;s Disease, Huntington&#39;s Disease, Parkinson&#39;s Disease, AIDS dementia, retinal disease, diabetic peripheral neuropathy, multiple sclerosis, stroke, acute thromboembolic stroke, focal ischemia, global ischemia, transient ischemic attack, ischemia resulting from surgery, head trauma, spinal trauma, hypoxia, fetal hypoxia, and neuroprotection., the compounds having the structure:  
                 
 
     wherein X is —CH 2 — or a bond; Y is —(CH 2 )m— or —(CH 2 )—O—(CH 2 )—; m 0 or 1; n is 0 or 1; R 1  and R 2  are independently selected from optionally substituted aryl or heteroaryl; the optical isomers and the pharmaceutically acceptable salts thereof.

[0001] This application is a continuation of U.S. Application Ser. No.09/706,683, filed Nov. 6, 2000, pending, which claims the benefit ofU.S. Provisional Application No. 60/228,820, filed Nov. 12, 1999 andU.S. Provisional Application No. 60/219,348, filed Nov. 18, 1999.

[0002] This invention relates to novel branched adamantyl, noradamantylaryl and aralkylpiperazines having serotonin 5-HT_(1A) activity. Moreparticularly, the present invention relates to compounds and methodsusing them to provide neuroprotection and prevent, inhibit or limitprocesses of neurodegeneration in mammals.

INTRODUCTION

[0003] Compounds having selective agonist and partial agonist activityat the 5-HT_(1A) receptor have established a presence in the marketplaceas effective anxiolytic agents (buspirone, Buspar®, U.S. Pat. No.3,717,634). Evidence generated over the past 20 years supports thehypothesis that 5-HT_(1A) agonists and partial agonists may find use inthe treatment of several diseases such as anxiety, depression,schizophrenia, sexual dysfunction, cognitive deficits resulting fromneurodegenerative diseases like Alzheimer's Disease, nausea andvomiting, sleep disorders, pain, obesity, pain, addiction/withdrawl andin the treatment of prostate cancer (for recent reviews, see: Rasmussen,K. and Rocco, V. P., Recent Progress in Serotonin (5-HT)_(1A) ReceptorModulators, In: Annual Reports in Medicinal Chemistry, Volume 30,Bristol, J. A., ed., Academic Press, New York, 1995, pp. 1-9; Schaus, J.M. and Bymaster, F. P., Latest Developments in Serotonin ReceptorModulation, In: Annual Reports in Medicinal Chemistry, Volume 33,Bristol, J. A., ed., Academic Press, New York, 1998, pp. 21-30).

[0004] More recent evidence now indicates that 5-HT_(1A) agonists andpartial agonists act in other disease states and conditions by virtue oftheir ability to inhibit the release of glutamate. 5-HT_(1A) agonistsand partial agonists may be used to treat conditions arising from thedysfunction of the glutamate neurotransmitter system or the aberrantrelease of glutamate.

[0005] Glutamate is the predominant neurotransmitter in the centralnervous system and it plays an important role in neuroplasticity. Assuch, excessive extracellular levels of glutamate have been associatedwith the pathophysiology of both acute neurodegenerative disorders suchas stroke, transient ischemic attack and spinal/brain trauma, as well aschronic neurodegenerative disorders such as epilepsy, Alzheimer'sDisease, amyotrophic lateral sclerosis, Huntington's Disease,Parkinson's Disease, AIDS dementia and retinal diseases (Holt, W. F. etal., Glutamate in Health and Disease: The Role of Inhibitors. In:Neuroprotection in CNS Diseases. Bar, P. R. and Beal, M. F., ed., MarcelDekker, Inc., New York 1997, pp. 87-119; Engelsen, B. A. et al.,Alterations in Excitatory Amino Acid Transmitters in Human NeurologicalDisease and Neuropathology. In: Neurotoxicity of Excitatory Amino Acids.Guidotti, A., ed., Raven Press Ltd., New York 1990, pp. 311-332; Ince,P. G. et al., The Role of Excitotoxicity in Neurological Disease. Res.Contemp. Pharmacother. 1997, 8, 195-212; Meldrum, P. S. The GlutamateSynapse as a Therapeutical Target: Perspective for the Future. Prog.Brain. Res. 1998, 441-458). Compounds which inhibit or attenuate therelease of glutamate represent potential neuroprotective agents for thetreatment of ischemia resulting from stroke, transient ischemic attack,brain/spinal trauma and fetal hypoxia (Koroshetz, W. J. and Moskowitz,M. A., Emerging Treatment for Stroke in Humans. Trends in Pharmacol. Sci1996, 17, 227-233; Dunn, C. D. R. Stroke: Trends, Treatments andMarkets. Scrip Reports, PJB Publications, Richmond 1995). Ischemia canalso result from surgery where the blood flow must be halted for aperiod of time (e.g., cardiac by-pass surgery) due to the resultinganoxia and hypoglycemia (Arrowsmith, J. E. et al., Neuroprotection ofthe Brain During Cardiopulmonary Bypass. A Randomized Trial ofRemacemide During Coronary Artery Bypass in 171 Patients, Stroke 1998,29, 2357-2362, and references cited within).

[0006] Serotonin 5-HT_(1A) receptors are located in brain areas whichare highly sensitive to ischemia, such as the hippocampus and cerebralcortex. Activation of this receptor subtype results in neuronalhyperpolarization and a concomitant inhibition of neuronal activity(DeVry, J. 5-HT1A Receptor Agonists: Recent Developments andControversial Issues. Psychopharmacology 1995, 121, 1-26). Moreover, ithas been demonstrated that 5-HT_(1A) receptor agonists and partialagonists are able to attenuate glutamate release, most likely throughactivation of 5-HT_(1A) receptors located on glutamatergic terminals(Matsuyama, S. et al., Regulation of Glutamate Release via NMDA and5-HT_(1A) Receptors in Guinea Pig Dentate Gyrus. Brain Res. 1996, 728,175-180) and that a number of 5-HT_(1A) agonists and partial agonistsexert neuroprotective properties in vivo (DeVry, J. et al., BAY x 3702,Drugs of the Future 1997, 22, 341-349, and references cited within).

[0007] Therefore, in addition to its well established potentialtherapeutic applications, compounds which possesses 5-HT_(1A) agonist orpartial agonist activity may be used as neuroprotective agents as wellas a means for treating psychosis.

[0008] Preclinical models, neurochemical hypotheses and brainlocalization have predicted a number of potential therapeutic targetsfor serotonin 5-HT_(1A) antagonists as well. These targets include thecognitive deficits observed in Alzheimer's Disease, anxiety, depression,schizophrenia and urinary incontinence (for a review see Schechter, L.E. and Kelly, M. G., An Overview of 5-HT_(1A) Receptor Antagonists:Historical Perspective and Therapeutic Targets, in Serotonin—CurrentDrugs ID Research Alert 1997, 2, 299-309).

DESCRIPTION OF THE INVENTION

[0009] In accordance with this invention, there is provided a set ofnovel compounds, including their enantiomers, which have activity asserotonin 5-HT_(1A) agonists, partial agonists and antagonists.Compounds of the present invention are described by the formula I:

[0010] wherein:

[0011] X is selected from —CH₂— or a chemical bond;

[0012] Y is selected from —(CH₂)_(m)— or —(CH₂)—O—(CH₂)—;

[0013] m is selected from the integer 0 or 1;

[0014] n is selected from the integer 0 or 1;

[0015] R₁ and R₂ are independently selected from the group consisting ofaryl or heteroaryl of from 5-10 atoms optionally substituted with F, Cl,Br, I, —OH, —NH₂, —CO₂H, —CO₂—C₁-C₆ alkyl, —CN, —NO₂, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ perhaloalkyl, OR₃, or C₁-C₆ perhaloalkoxy;

[0016] R₃ is selected from the group consisting of H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl, mono or bicyclic heteroaryl, C₇-C₁₄aralkyl, and mono or bicyclic heteroaralkyl, where the aryl orheteroaryl group is optionally substituted with one to threesubstituents independently selected from the group consisting of F, Cl,Br, I, CN, —NH₂, —NO₂, —OH, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆perhaloalkyl, C₁-C₆ alkoxy, and C₁-C₆ perhaloalkoxy;

[0017] the optical isomers;

[0018] and the pharmaceutically acceptable salts thereof.

[0019] The term C₆-C₁₀ aryl includes phenyl and naphthyl. Monocyclicheteroaryl means a 5-6 membered heteroaryl group having from 1-3heteroatoms selected independently from N, O, and S, such as pyridine,pyrrole, thiophene, furan, imidazole, oxazole, pyrimidine, pyridazine,pyrazine, thiazole and oxathiazole. Bicyclic heteroaryl includes phenylfused to a monocyclic 5-6 membered heteroaryl group or a 5-6 memberedheteroaryl group fused to another 5-6 membered heteroaryl group,including, but not limited to indole, quinoline, isoquinoline,benzofuran, benzodioxan, benzothiophene, benzimidazole, naphthyridine,and imidazopyridine. The term C₇-C₁₄ aralkyl means a C₁-C₄ alkyl grouphaving a phenyl or naphthyl group as a substituent, and the termheteroaralkyl means a C₁-C₄ alkyl group having a mono or bicyclicheteroaryl group as defined above as a substituent.

[0020] Among the preferred compounds of this invention are those of theformula:

[0021] Y is selected from —(CH₂)_(m)— or —(CH₂)—O—(CH₂)—;

[0022] m is selected from the integer 0 or 1;

[0023] n is selected from the integer 0 or 1;

[0024] R₁ is phenyl optionally substituted with F, Cl, Br, I, —OH, —NH₂,—CO₂H, —CO₂—C₁-C₆ alkyl, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ perhaloalkyl or C₁-C₆ perhaloalkoxy;

[0025] R₂ is selected from phenyl, napthyl, piperazinyl, pyridine,thiophene, furan, imidazole, oxazole, pyrrole, pyrimidine, pyridazine,pyrazine, thiazole or oxathiazole;

[0026] the optical isomers;

[0027] and the pharmaceutically acceptable salts thereof.

[0028] Further preferred compounds of this invention are those of theformula:

[0029] Y is selected from —CH₂—;

[0030] m is selected from the integer 0 or 1;

[0031] n is selected from the integer 0 or 1;

[0032] R₁ is phenyl optionally substituted with F, Cl, Br, I, —OH, —NH₂,—CO₂H, —CO₂—C₁-C₆ alkyl, —CN, —NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ perhaloalkyl or C₁-C₆ perhaloalkoxy;

[0033] R₂ is phenyl or pyrimidinyl;

[0034] the optical isomers or a pharmaceutically acceptable saltthereof.

[0035] Optical isomers of the invention compounds can be selectivelysynthesized or separated using conventional procedures known to thoseskilled in the art of organic synthesis.

[0036] The pharmaceutically acceptable salts of the invention compoundsinclude the conventional acid addition salts which are formed from aninvention compound and a pharmaceutically acceptable organic orinorganic acid. The acid addition salts include, but is not limited to,the acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,dodecylsulfate, ethanesulfonate, fumarate, glycerophosphate, phosphate,hemisulfate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate,methanesulfonate, nicotinate, oxalate, pamoate, pectinate, pivalate,propionate, succinate, tartrate, and tosylate. Also the basicnitrogen-containing groups may be quaternized with such agents as loweralkyl halides, dialkyl sulfates, long chain halides such as laurylbromide, aralkyl halides like benzyl and phenethyl bromides.

[0037] Methods of treatment of this invention include thoseglutamate-mediated maladies wherein inhibition of glutamate release isdesireable. These methods may be characterized as methods for inhibitingor limiting neuronal glutamate release in a mammal, the methodcomprising administering to the mammal, preferably to a human patient, apharmaceutically effective amount of a compound of this invention, or apharmaceutically effective salt thereof.

[0038] As such, these compounds may be useful in the treatment ofseveral diseases such as anxiety, depression, schizophrenia, sexualdysfunction, cognitive deficits resulting from neurodegenerativediseases including Alzheimer's Disease, nausea and vomiting, epilipsy,sleep disorders, obesity, pain, addiction/withdrawal, urinaryincontinence, prostate cancer, and ischemia resulting from acute stroke,transient ischemic attack, head and spinal trauma, fetal hypoxia,neuronal hypoxia, cardiac surgery or any other surgical technique whichrequires halting the blood flow for a period of time.

[0039] The methods of this invention are also useful in inhibiting orlimiting the chronic neurodegenerative actions associated withAlzheimer's Disease, Huntington's Disease, Parkinson's Disease,epilepsy, amyotrophic lateral sclerosis, AIDS dementia as well asretinal diseases. Therefore, this invention also comprises methods oftreatment for each of these maladies, the methods comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of this invention, or a pharmaceutically acceptablesalt thereof.

[0040] The compounds of this invention may also be used in the mediationor inhibition of glutamate activity associated with the maladies knownas chronic, neuropathic or persistant pain, including its actions infibromyalgia, postherpetic neuralgia, reflex sympathetic dystrophy,diabetic peripheral neuropathy, etc.

[0041] Of particular interest is methods of using the compounds of thisinvention to treat, prevent, limit, inhibit, delay or alleviateneurodegeneration in a mammal, the methods comprising administering to amammal in need thereof a pharmaceutically effective amount of a compoundof this invention, or a pharmaceutically acceptable salt thereof. Thesemethods include those in which the neurodegenerative disease or disorderis acute or chronic. Included are those instances in which theneurodegeneration results from stroke, including thromboembolic stroke,focal ischemia, global ischemia and tranient ischemic attack. Alsoincluded are those neurodegenerative disorders such as ischemiaresulting from a surgical technique involving prolonged halt of bloodflow to the brain, head or spinal trauma, or hypoxia, including fetalhypoxia.

[0042] For their ability to inhibit, prevent or limit further neuraldegradation in the hypoxic and ischemic events of the maladies describedabove, the methods of treatment of this invention may also becharacterized as methods for providing or inducing neuroprotection in amammal, as their activity reduces or inhibits the glutamate-mediated orglutamate-related degeneration which would naturally occur.

[0043] The compound of formula I can be prepared by conventionalchemical methods which are well known to those skilled in the art ofchemistry using chemicals that are either commercially available orreadily prepared following standard literature procedures. For example,the compounds may be synthesized in four steps (Scheme 1) starting fromthe appropriate phenylalanine, phenylglycine or heteroaryl-substitutedalanine or heteroaryl-substituted glycine which has been protected onthe nitrogen atom with a suitable protecting group such as thet-butoxycarbonyl group (BOC). This material is coupled to theappropriately substituted arylpiperazine or aralkyl piperazine using asuitable coupling catalyst, such as dicyclohexylcarbodiimide (DCC) toafford compound 1. Removal of the BOC group under acidic conditionsfollowed by reduction using an appropriate reducing agent such aslithium aluminum hydride or a borane complex leads to the penultimateintermediate 3. Subsequent acylation of 3 with a suitable acylatingagent such as adamantane-1-carboxylic acid chloride ornoradamantyl-3-carboxylic acid chloride gives compounds of formula I,which are isolated as acceptable salts.

[0044] In cases where the R₂ grouping is not compatible with thereductive conditions required for the conversion of intermediate 2 tointermediate 3, it may be introduced after the reduction of the amide byinitially protecting the NH group of the piperazine with a benzyl moiety(Scheme 2). This benzyl group can then be removed under catalytichydrogenation conditions and the R₂ group incorporated into the moleculeto give the final products.

[0045] The starting materials required for the synthesis of thecompounds of formula I are either commercially available or readilyobtained using conventional methods described in the literature. Thepreparative method described above is not meant to be restrictive butonly illustrative since other methods of preparing the compounds offormula I may be obvious to those skilled in the art of chemistry. Forexample, while numerous, N-protected amino acids are commerciallyavailable, the protecting group may alternatively be introduced onto anamino acid using conventional methods which are well described in theliterature. Other protecting groups such as carbobenzyloxy (CBZ) may beemployed to protect the nitrogen grouping in the first step of thesynthesis and many other coupling catalysts may serve to effect thereaction. Exact reagents required to de-protect the amine group ofintermediate 1 once the coupling has been effected will depend on theprotecting group used and the substituents present in the molecule.Other reducing agents besides LAH or borane may serve to accomplish thereduction of intermediate 2. Finally, the introduction of theacyl-adamantyl or acyl-noradamantyl group may be accomplished accordingto the general method described in Scheme 1 using one of many possibleacylating derivatives, which include but are not limited to acid halides(e.g., acid chloride), anhydrides and activated esters and amides orthrough the use of adamantyl- or noradamantyl carboxylic acid and anappropriate coupling catalyst.

[0046] Since numerous chirally pure amino acids and protected aminoacids are either commercially available or known in the literature, thepure optical isomers of the compounds of formula I may be obtainedstereospecifically by beginning the synthesis with chirally purestarting materials. Alternatively, the optical isomers of the compoundsof formula I may be obtained by conventional separation methods whichare well known to those skilled in the art of synthetic chemistry. Thesemethods include but are not restricted to crystallization of a mixtureof diastereomeric salts, enzymatic resolution, chromatography of one ofthe intermediates or the final product on a chiral column, or formationand separation of a diastereomeric mixture followed by conversion backto the chirally pure material.

[0047] The following examples are included for illustrative purposesonly and are not intended to be considered as limiting to thisdisclosure in any way.

EXAMPLE 1(R)-N-[1-(Phenylmethyl)-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]tricyclo[3.3.1.1^(3,7))]-decane-1-carboxamideDihydrochloride Dihydrate

[0048] (R)-Phenylalanine-N-[4-(phenylmethyl)-1-piperizinyl]carboxamideDihydrochloride. D-Phenylalanine-N-t-butoxycarboxamide (13.25 g, 50mmol) and 1-benzylpiperazine (8.8 g, 50 mmol) were dissolved in 125 mLof dry dichloromethane and cooled in an ice bath. The stirred mixturewas then treated with a solution of diethylcyanophosphonate (8.97 g, 55mmol) in 50 mL of dry dichloromethane over a period of 45 minutes. Asolution of N-methylmorpholine (5.55 g, 55 mmol) in 50 mL of drydichloromethane was then added over a period of one hour. The resultingreaction mixture was stirred overnight, during which time it came up toroom temperature. The solution was then washed with 100 mL of 10%aqueous potassium carbonate, dried over anhydrous sodium sulfate, andconcentrated on a rotary evaporator to yield 26 g of the crudeintermediateBOC-(R)-phenylalanine-N-(4-benzyl-1-piperazinyl)carboxamide. This oilwas dissolved in 200 mL of dichloromethane and treated with a 4.6 Nsolution of HCl in ethyl acetate (350 mL). After stirring at roomtemperature for one hour (at which time CO₂ evolution ceased), 250 mL ofdry diethyl ether was added. The desired dihydrochloride salt of(R)-phenylalanine-N-[(4-phenylmethyl)-1-piperazinyl]-carboxamide (18.9g, 95%) precipitated and was isolate by filtration, washed with diethylether, and dried in vacuo: mp=140-150° C.; [α-D]²⁵=−3.7° (c=1, MeOH); MSm/z=323 (M⁺).

[0049](R)-[1-(Phenylmethyl)-2-[(4-phenylmethyl)-1-piperazinyl]ethyl]amine. Asolution of(R)-phenylalanine-N-[(4-phenylmethyl)-1-piperazinyl]carboxamidedihydrochloride (18.8 g, 47.4 mmol) in 230 mL of 1 Mborane/tetrahydrofuran was refluxed with stirring for four hours under anitrogen atmosphere. The resulting mixture was cooled in an ice bath andquenched by slow addition of 150 mL of 2N aqueous HCl. The resultingmixture was then refluxed with stirring overnight. The tetrahydrofuranwas removed under reduced pressure. The filtrate was washed with five 50mL portions of dichloromethane and then made strongly basic with 50%aqueous sodium hydroxide solution. The resulting alkaline mixture wasthen extracted with three 100 mL portions of dichloromethane. Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated on a rotary evaporator to yield the desired(R)-[1-(phenylmethyl)-2-[(4-phenylmethyl)-1-piperazinyl]ethyl]amine(17.1 g, 95%) as a yellow oil which was used without furtherpurification. A sample of this oil was converted to the trihydrochloridesesquihydrate salt with ethyl acetate/HCl for characterization:m.p.=183-185 C; [α-D]²⁵ =−27.7 (c=1, MeOH); MS m/z=309 (M⁺). Analysisfor C₂₀H₂₅N₃O.3 HCl.1½ H₂O Calculated: C: 53.83; H: 7.40; N: 9.42 Found: C: 54.22; H: 7.11; N: 9.24.

[0050](R)-N-[1-(Phenylmethyl)-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]tricyclo-[3.3.1.1^(3,7))]-decane-1-carboxamideDihydrochloride Dihydrate. To an ice-cooled solution of1-adamantanecarboxylic acid (5.1 g, 50 mmol) and(R)-[1-(phenylmethyl)-2-[(4-phenylmethyl)-1-piperazinyl]ethyl]amine (9.6g, 25 mmol) in 60 mL of dry dichloromethane was added, with stirring,diethylcyanophosphonate (4.1 g, 25 mmol) over a period of thirtyminutes. Upon completed addition, N-methylmorpholine (2.53 g, 25 mmol)was added and the resulting mixture was stirred overnight during whichtime it came up to room temperature. The reaction mixture was thenwashed with 100 mL of 10% aqueous potassium carbonate solution followedby 100 mL of water. The resulting organic layer was dried over anhydroussodium sulfate and concentrated on a rotary evaporator. The desiredproduct was isolated by chromatography on silica gel using a gradient ofethyl acetate and hexane and then converted to its dihydrochloridedihydrate salt (6.30 g, 44%) with HCl/ethyl acetate: mp=261-263° C.;[α-D]²⁵=−12.5° (c=1, MeOH); CIMS m/z=472 (MH⁺). Analysis for C₃₁H₄₁N₃O.2HCl.2 H₂O Calculated: C: 64.12; H: 8.16; N: 7.24  Found: C: 63.92; H:8.30; N: 6.90.

EXAMPLE 2(S)-N-[1-(Phenylmethyl)-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]tricyclo[3.3.1.1^(3,7))]-decane-1-carboxamideDihydrochloride Dihydrate

[0051] Beginning with L-phenylalanine-N-t-butoxycarboxamide,(S)-N-[1-(phenylmethyl)-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]tricyclo[3.3.1.1^(3,7))]-decane-1-carboxamidewas prepared using a synthetic sequence identical to that described forthe synthesis of Example 1. It was isolated as its dihydrochloridedihydrate salt in 9% overall yield: mp 263-266° C.; [α-D]²⁵=+11.3(c=1.03, MeOH); CIMS m/z=472 (MH⁺). Analysis for C₃₁H₄₁N₃O.2 HCl.2 H₂OCalculated: C: 64.12; H: 8.16; N: 7.24  Found: C: 64.13; H: 7.86; N:7.27.

EXAMPLE 3(R)-N-[1-(Phenylmethyl)-2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl]tricyclo[3.3.1.1^(3,7))]-decane-1-carboxamideHemihydrate

[0052] The compound of Example 1 (4.5 g, 7.84 mmol) was hydrogenatedover 10% Pd/C (1 g) in 200 mL of ethanol on a Parr shaker at a pressureof 36 psi overnight. The catalyst was removed by filtration throughCelite and the mixture concentrated on a rotary evaporator to yield thecrude(R)-N-[1-(phenylmethyl)-2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl]tricyclo[3.3.1.1^(3,7))]-decane-1-carboxamide(2.8 g) as an oil. This oil was dissolved in 50 mL of drydimethylformamide. To the stirred solution was added 2-chloropyrimidine(1.05 g, 9.2 mmol), anhydrous potassium carbonate (12.4 g, 90 mmol), andtriethylamine (1 mL), and the resulting mixture was heated at 70° C.overnight. The DMF was removed on a rotary evaporator and the residuewas triturated with water. The resulting precipitate was washed withwater, air-dried, and recrystallized from 50% aqueous methanol to yieldthe desired compound as a hemihydrate: mp 172-175° C.; [α-D]²⁵ = −9.7°(c = 1.07, MeOH); CIMS m/z = 460 (MH⁺). Analysis for C₂₈H₃₅N₅O.½ H₂OCalculated: C: 71.76; H: 8.17; N: 14.95  Found: C: 71.90; H: 8.02; N:14.82.

EXAMPLE 4(S)-N-[1-(Phenylmethyl)-2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl]tricyclo[3.3.1.1^(3,7))]-decane-1-carboxamide

[0053] Beginning with the compound of Example 2,(S)-N-[1-(phenylmethyl)-2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl]tricyclo[3.3.1.1^(3,7))]-decane-1-carboxamidewas prepared using a synthetic sequence identical to that described forthe synthesis of Example 3. It was isolated in 78% overall yield: mp172-175° C.; [α-D]²⁵=+7.20 (c=1.03, MeOH); CIMS m/z=460 (MH⁺). Analysisfor C₂₈H₃₇N₅O Calculated: C: 73.17; H: 8.11; N: 15.24  Found: C: 72.87;H: 7.90; N: 15.00.

EXAMPLE 5(R)-N-[1-((Phenylmethoxy)methyl)-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]tricyclo-[3.3.1.1^(3,7))]-decane-1-carboxamideDihydrochloride Dihydrate

[0054] Beginning with D-O-benzylserine-N-t-butoxycarboxamide,(R)-N-[1-((phenylmethoxy)-methyl)-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-tricyclo-[3.3.1.1^(3,7))]-decane-1-carboxamidewas prepared using a synthetic sequence identical to that described forthe synthesis of Example 1. It was was converted to its dihydrochloridedihydrate salt with ethyl acetate/HCl and isolated in 5% overall yield:mp 140-142° C.; [α-D]²⁵=+19.0 (c=0.98, MeOH); CIMS m/z=502 (MH⁺).Analysis for C₃₂H₄₃N₃O₂.2 HCl.2 H₂O Calculated: C: 62.94; H: 8.08; N:6.88  Found: C: 62.74; H: 8.07; N: 6.86.

EXAMPLE 6 (R)-Adamantane-1-carboxylic acid[1-(phenylmethyl)-2-[4-(2-methoxyphenyl)-piperazinyl]ethyl]-amideHemifumarate Hemihydrate

[0055](R)-[1-(Phenylmethyl)-2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxo-ethyl]-carbamicacid tert-butyl ester. To a 0° C. solution ofD-phenylalanine-N-t-butoxy-carboxamide (10.0 g, 37.7 mmol),1-hydroxybenzotriazole (8.66 g, 64.1 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.20 g,37.7 mmol) in dry dimethylformamide (50 mL) under a nitrogen atmosphere,was added 1-(2-methoxyphenyl)-piperazine (9.50 g, 41.5 mmol), followedby N-methylmorpholine (7.62 g, 75.4 mmol). The resulting mixture wasstirred under nitrogen overnight, during which time it came up to roomtemperature. The reaction mixture was diluted with ethyl acetate andthen washed with 0.1 N aqueous HCl, saturated aqueous sodium bicarbonateand saturated sodium chloride solution. The combined organic layersdried over anhydrous sodium sulfate and concentrated under reducedpressure to yield the desired product (16.57 g, 99% yield) as a yellowoil which was pure enough to use without further purification:[α-D]²⁵=−9.0 (c=1, MeOH); MS m/z=439 (M⁺). Analysis for C₂₅H₃₃N₃O₄Calculated: C: 68.31; H: 7.57; N: 9.56  Found: C: 68.09; H: 7.17; N:9.46.

[0056](R)-1-(Phenylmethyl)-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl)amine.A solution of(R)-[1-(phenylmethyl)-2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxo-ethyl]-carbamicacid tert-butyl ester (16.37 g, 37.3 mmol) in a mixture of dioxane (150mL)/4N aqueous HCl (150 mL) was stirred at room temperature for 6 hours.The reaction mixture was then concentrated under reduced pressure andthe aqueous mixture was extracted with diethyl ether. The combinedorganic extracts were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to yield the desired(R)-[1-(phenylmethyl)-2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxoethyl]aminehydrochloride (14.0 g, 100% yield) as an off-white solid, which was usedin the next step without further purification.

[0057] To a solution of(R)-[1-(phenylmethyl)-2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxo-ethyl]aminehydrochloride (14 g, 37.3 mmol) and triethylamine (7.53 g, 74.6 mmol) inanhydrous tetrahydrofuran (150 mL) under a nitrogen atmosphere wasadded, dropwise, a 1M solution of borane in tetrahydrofuran (131 mL,130.6 mmol). The resulting mixture was stirred at reflux for threehours, then allowed to stir at room temperature overnight. The resultingmixture was treated with 2N aqueous HCl (300 mL) for two hours and thelayers were separated. The acidic aqueous layer was washed with ethylacetate, made basic with 50% aqueous sodium hydroxide, and extractedwith ethyl acetate. The combined organic layers were washed withsaturated aqueous sodium chloride solution, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The desired product(11.0 g, 91.0% yield)was isolated as an off-white solid: m.p.=95-97° C.;[α-D]²⁵ = −36.7 (c = 1, MeOH); FAB MS m/z = 326 (MH+). Analysis forC₂₀H₂₇N₃O Calculated: C: 73.80; H: 8.37; N: 12.77 Found: C: 73.15; H:8.34; N: 12.68

[0058] (R)-Adamantane-1-carboxylic acid[1-(phenylmethyl)-2-[4-(2-methoxyphenyl)-piperazinyl]ethyl]-amideHemifumarate Hemihydrate. To a solution of(R)-1-(phenylmethyl)-2-[4-(2-methoxyphenyl)-1-piperazinyl)ethyl]amine(0.25 g, 0.77 mmol) and triethylamine (0.16 g, 1.54 mmol) in anhydrousdichloromethane (15 mL) under a nitrogen atmosphere at 0 C. was added asolution of 1-adamantane-carboxylic acid chloride (0.17 g, 0.84 mmol) indichloromethane (5 mL). The resulting solution was allowed to stirovernight under nitrogen, during which time it came up to roomtemperature. The reaction mixture was then concentrated under reducedpressure, diluted with ethyl acetate and washed with water. The organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The desired product was purified by flashchromatography on silica gel (ethyl acetate/hexane) and converted to itshemifumarate hemihydrate salt with fumaric acid/ethanol to yield 0.30 g(71% yield) as a white solid: m.p.=153-155° C.; [α-D]²⁵=−9.0 (c=1,MeOH); MS m/z=487 (M+). Analysis for C₃₁H₄₁N₃O₂.½ C₄O₄.½ H₂O Calculated:C: 71.45; H: 8.00; N: 7.57  Found: C: 71.26; H: 8.05; N: 7.42.

EXAMPLE 7 (S)-Adamantane-1-carboxylic acid[1-(phenylmethyl)-2-[4-(2-methoxyphenyl)-piperazinyl]ethyl]-amideHemifumarate Hydrate

[0059] This compound was prepared using an identical synthetic sequenceto that described for Example 6 starting withL-phenylalanine-N-t-butoxy-carboxamide. The overall yield was 61% andthe compound (an off-white solid) was isolated as the hemifumaratehydrate salt: m.p.=157-159° C.; [α-D]²⁵=+9.5 (c=1, MeOH); FAB MS m/z=488(MH⁺). Analysis for C₃₁H₄₁N₃O₂.½ C₄O₄.H₂O Calculated: C: 70.31; H: 8.05;N: 7.45  Found: C: 70.21; H: 8.04; N: 7.11.

[0060] In Vitro Data

[0061] Affinity for the serotonin 5-HT_(1A) receptor was established byassaying the test compound's ability to displace [³H]-8-OH-DPAT from itsbinding site on the receptor complex in rat hippocampal membranehomogenates according to the method described in U.S. Pat. No.5,482,940. The compounds of this invention displayed high affinity forthe 5-HT_(1A) receptor, as exemplified by the data given in Table 1.

[0062] Some of the compounds of this invention displayed serotonin5-HT_(1A) agonist activity, as measured by the test compounds's abilityto stimulate the binding of [³⁵S]-GTPγS to the 5-HT_(1A) receptor-Gprotein complex in CHO cells stably transfected with the human 5-HT_(1A)receptor following a variation of the procedure described by Lazerinoand Birdsall (Br. J. Pharmacol., 109, 1120 (1993)). Data are given inTable 1. Data are presented as the percent of TABLE 1 5-HT_(1A) Agonist5-HT_(1A) Antagonist Activity (GTPγS) Activity (GTPγS) % % 5-HT_(1A)Agonist Antagonist Example Affinity (IC₅₀) Activity EC₅₀ Activity EC₅₀ 1 2.3 nM 100% 36 nM 2 0.70 nM 51%  21 nM 3 0.43 nM 100% 2.0 nM 4  1.0 nM99% 2.4 nM 5   62 nM 49%  77 nM 6 0.21 nM 76% 2.0 nM 7 0.70 nM 85% 2.0nM

[0063] agonist activity observed relative to the effect obtained withthe 5-HT_(1A) full agonist 8-OH-DPAT and the corresponding EC₅₀ value.As can be seen from Table 1, the compounds of this invention are potent5-HT_(1A) ligands which display agonist and partial agonist activity inthe GTPγS assay.

[0064] Some of the compounds of this invention displayed serotonin5-HT_(1A) antagonist activity, as measured by the test compound'sability to block the stimulation of the binding of [³⁵S]-GTP S to the5-HT_(1A) receptor-G protein complex induced by the 5-HT_(1A) fullagonist 8-OH-DPAT in CHO cells stably transfected with the human5-HT_(1A) receptor following a variation of the procedure described byLazerino and Birdsall (Br. J. Pharmacol., 109, 1120 (1993)). Data aregiven in Table 1. As can be seen from Table 1, some of the compounds ofthis invention are potent 5-HT_(1A) ligands which display antagonistactivity in the GTP S assay.

[0065] These activities make the compounds of this invention useful forthe treatment of several diseases such as anxiety, depression,schizophrenia, sexual dysfunction, cognitive deficits resulting fromneurodegenerative diseases like Alzheimer's Disease, nausea andvomiting, epilipsy, sleep disorders, obesity, pain,addiction/withdrawal, urinary incontinence, prostate cancer, andischemia resulting from acute stroke, transient ischemic attack, headand spinal trauma, fetal hypoxia, cardiac surgery or any other surgicaltechnique which requires halting the blood flow for a period of time,and chronic neurodegenerative diseases such as Alzheimer's Disease,Huntington's Disease, Parkinson's Disease, amyotrophic lateralsclerosis, AIDS dementia as well as retinal diseases.

[0066] Pharmaceutical Composition

[0067] This invention also comprises pharmaceutical compositionscomprising pharmaceutically effective amounts of one or more compoundsof this invention, or a pharmacetically acceptable salt thereof, and oneor more pharmaceutically acceptable carriers or excipients. Thepharmaceutically effective amount of these compounds will be understoodto be an amount which provides an effective degree of neuroprotection ortreats, inhibits or limits the neurodegeneration in question. In humans,a daily dosage of from about 100 mg to about 1,500 mg per day may beadministered, preferably between about 300 mg and about 1,200 mg perday, more preferably between about 500 mg and 1,000 mg per day. Thesedosages may be administered in a single administration or divided intomultiple doses for sequential administration.

[0068] The compounds of the present invention may be administered orallyor parentally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders,tablet-disintegrating agents or encapsulating materials. In powders, thecarrier is a finely divided solid which is in admixture with the finelydivided active ingredient. In tablets, the active ingredient is mixedwith a carrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets may contain up to 99% of the active ingredient. Suitable solidcarriers include, for example, calcium phosphate, magnesium stearate,talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, lowmelting waxes and ion exchange resins. Liquid carriers may be used inpreparing solutions, suspensions, emulsions, syrups and elixirs. Theactive ingredient of this invention can be dissolved or suspended in apharmaceutically acceptable liquid carrier such as water, an organicsolvent, a mixture of both or pharmaceutically acceptable oils or fat.The liquid carrier can contain other suitable pharmaceutical additivessuch as solubilizers, emulsifiers, buffers, preservatives, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stabilizers or osmo-regulators. Suitable examplesof liquid carriers for oral and parenteral administration include water(particularly containing additives as above, e.g., cellulosederivatives, preferably sodium carboxymethyl cellulose solution),alcohols (including monohydric alcohols and polyhydric alcohols, e.g.,glycols) and their derivatives, and oils (e.g., fractionated coconut oiland arachis oil). For parenteral administration, the carrier can also bean oily ester such as ethyl oleate and isopropyl myristate. Sterileliquid carriers are used in sterile liquid form compositions forparenteral administration. Liquid pharmaceutical compositions, which aresterile solutions or suspensions can be utilized by, for example,intramuscular, intraperitoneal or subcutaneous injection. Sterilesolutions can also be administered intravenously. Oral administrationmay be either in liquid or solid composition form. Preferably, thepharmaceutical compositions containing the present compounds are in unitdosage form, e.g., as tablets or capsules. In such form, the compositionis sub-divided in unit dosages containing appropriate quantities of theactive ingredients. The unit dosage forms can be packaged compositions,for example, packaged powders, vials, ampoules, prefilled syringes orsachets containing liquids. Alternatively, the unit dosage form can be,for example, a capsule or tablet itself, or it can be the appropriatenumber of any such compositions in package form. The therapeuticallyeffective dosage to be used in the treatment of a specific disease orcondition must be subjectively determined by the attending physician.The variables involved include the specific condition(s) being treatedand the size, age and response pattern of the patient.

[0069] The present invention may be embodied in other specific formswithout departing from the spirit and essential attributes thereof andaccordingly, reference should be made to the appended claims, ratherthan to the foregoing specification, as indicating the scope of theinvention.

What is claimed:
 1. A compound of the formula:

wherein: Y is selected from —CH₂— or —CH₂—O—CH₂—; n is selected from the integer 0 or 1; R₁ is phenyl optionally substituted with F, Cl, Br, I, —OH, —NH₂, —CO₂H, —CO₂—C₁-C₆ alkyl, —CN, —NO₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₁-C₆ perhaloalkyl or C₁-C₆ perhaloalkoxy; R₂ is phenyl, pyrimidinyl, pyridyl, pyridazinyl, or pyrazinyl optionally substituted with F, Cl, Br, I, —OH, —NH₂, —CO₂H, —CO₂—C₁-C₆ alkyl, —CN, —NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ perhaloalkyl, or C₁-C₆ perhaloalkoxy; and the optical isomers or a pharmaceutically acceptable salt thereof.
 2. A compound of claim 1 wherein: R₁ is phenyl optionally substituted with F, Cl, Br, I, —OH, —NH₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ perhaloalkyl or C₁-C₆ perhaloalkoxy; R₂ is phenyl or pyrimidinyl optionally substituted with F, Cl, Br, I, —OH, —NH₂, —CO₂H, —CO₂—C₁-C₆ alkyl, —CN, —NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ perhaloalkyl, or C₁-C₆ perhaloalkoxy; and the optical isomers or a pharmaceutically acceptable salt thereof.
 3. A compound of claim 1 wherein: R₁ is phenyl optionally substituted with F, Cl, Br, I, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ perhaloalkyl or C₁-C₆ perhaloalkoxy; R₂ is phenyl or pyrimidinyl, optionally substituted with F, Cl, Br, I, C₁-C₆ alkyl, C₁-C₆ perhaloalkyl, or C₁-C₆ perhaloalkoxy; and the optical isomers or a pharmaceutically acceptable salt thereof.
 4. A compound of claim 1 which is (R)-N-[1-(Phenylmethyl)-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]tricyclo[3.3.1.1^(3,7))]-decane-1-carboxamide Dihydrochloride Dihydrate.
 5. A compound of claim 1 which is (R)-N-[1-(Phenylmethyl)-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]tricyclo-[3.3.1.1^(3,7))]-decane-1-carboxamide Dihydrochloride Dihydrate.
 6. A compound of claim 1 which is (S)-N-[1-(Phenylmethyl)-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]tricyclo[3.3.1.1^(3,7))]-decane-1-carboxamide Dihydrochloride Dihydrate.
 7. A compound of claim 1 which is (R)-N-[1-(Phenylmethyl)-2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl]tricyclo[3.3.1.1^(3,7))]-decane-1-carboxamide Hemihydrate.
 8. A compound of claim 1 which is (S)-N-[1-(Phenylmethyl)-2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl]tricyclo[3.3.1.1^(3,7))]-decane-1-carboxamide.
 9. A compound of claim 1 which is (R)-N-[1-((Phenylmethoxy)methyl)-2-[4-(phenylmethyl)-1-piperazinyl]ethyl]tricyclo-[3.3.1.1^(3,7))]-decane-1carboxamide Dihydrochloride Dihydrate.
 10. A compound of claim 1 which is (R)-Adamantane-1-carboxylic acid [1-(phenylmethyl)-2-[4-(2-methoxyphenyl)-piperazinyl]ethyl]-amide Hemifumarate Hemihydrate.
 11. A compound of claim 1 which is (S)-Adamantane-1-carboxylic acid [1-(phenylmethyl)-2-[4-(2-methoxyphenyl)-piperazinyl]ethyl]-amide Hemifumarate Hemihydrate.
 12. A compound of claim 1 which is (S)-Adamantane-1-carboxylic acid [1-(phenylmethyl)-2-[4-(2-methoxyphenyl)-piperazinyl]ethyl]-amide Hemifumarate Hydrate.
 13. A pharmaceutical composition comprising a) a pharmaceutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof; and b) one or more pharmaceutically acceptable carriers or excipients.
 14. A method of treating a neurodegenerative disorder selected from Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, or AIDS dementia, comprising administering a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutical salt thereof, to a patient in need of said treatment.
 15. A method of treating a neurodegenerative disorder selected from retinal disease or amyotrophic lateral sclerosis comprising administering to a patient in need of said treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutical salt thereof:

wherein X is selected from —CH₂— or a chemical bond; Y is selected from —(CH₂)_(m)— or —(CH₂)—O—(CH₂)—; m is selected from the integer 0 or 1; n is selected from the integer 0 or 1; R₁ and R₂ are independently selected from the group consisting of aryl, monocyclic heteroaryl having 5-6 ring atoms of which 1-3 ring atoms are independently selected from the group consisting of N, S and O, and bicyclic heteroaryl having a phenyl ring fused to a monocyclic heteroaryl ring as defined above, optionally substituted with F, Cl, Br, I, —OH, —NH₂, —CO₂H, —CO₂—C₁-C₆ alkyl, —CN, —NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perhaloalkyl, OR₃, or C₁-C₆ perhaloalkoxy; R₃ is selected from the group consisting of H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl, monocyclic heteroaryl having 5-6 ring atoms of which 1-3 ring atoms are independently selected from the group consisting of N, S and O, and bicyclic heteroaryl having a phenyl ring fused to a monocyclic heteroaryl ring as defined above, C₇-C₁₄ aralkyl, and mono or bicyclic heteroaralkyl consisting of a C₁-C₄ alkyl having a substituent which is a mono or bicyclic heteroaryl as defined above, where the aryl or heteroaryl group is optionally substituted with one to three substituents independently selected from the group consisting of F, Cl, Br, I, CN, —NH₂, —NO₂, —OH, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perhaloalkyl, C₁-C₆ alkoxy, and C₁-C₆ perhaloalkoxy; and the optical isomers or a pharmaceutically acceptable salt thereof.
 16. A method of treating a neurodegenerative disorder selected from epilepsy, ischemia resulting from a surgical technique involving prolonged halt of blood flow to the brain, head trauma, spinal trauma, hypoxia, comprising administering to a patient in need of said treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutical salt thereof:

wherein X is selected from —CH₂— or a chemical bond; Y is selected from —(CH₂)_(m)— or —(CH₂)—O—(CH₂)—; m is selected from the integer 0 or 1; n is selected from the integer 0 or 1; R₁ and R₂ are independently selected from the group consisting of aryl, monocyclic heteroaryl having 5-6 ring atoms of which 1-3 ring atoms are independently selected from the group consisting of N, S and O, and bicyclic heteroaryl having a phenyl ring fused to a monocyclic heteroaryl ring as defined above, optionally substituted with F, Cl, Br, I, OH, —NH₂, —CO₂H, —CO₂—C₁-C₆ alkyl, —CN, —NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆perhaloalkyl, OR₃, or C₁-C₆ perhaloalkoxy; R₃ is selected from the group consisting of H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl, monocyclic heteroaryl having 5-6 ring atoms of which 1-3 ring atoms are independently selected from the group consisting of N, S and O, and bicyclic heteroaryl having a phenyl ring fused to a monocyclic heteroaryl ring as defined above, C₇-C₁₄ aralkyl, and mono or bicyclic heteroaralkyl consisting of a C₁-C₄ alkyl having a substituent which is a mono or bicyclic heteroaryl as defined above, where the aryl or heteroaryl group is optionally substituted with one to three substituents independently selected from the group consisting of F, Cl, Br, I, CN, —NH₂, —NO₂, —OH, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perhaloalkyl, C₁-C₆ alkoxy, and C₁-C₆ perhaloalkoxy.
 17. The method of claim 16 wherein the hypoxia is fetal hypoxia.
 18. A method of treating chronic pain comprising administering to a patient in need of said treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutical salt thereof:

wherein X is selected from —CH₂— or a chemical bond; Y is selected from —(CH₂)m— or —(CH₂)—O—(CH₂)—; m is selected from the integer 0 or 1; n is selected from the integer 0 or 1; R₁ and R₂ are independently selected from the group consisting of aryl, monocyclic heteroaryl having 5-6 ring atoms of which 1-3 ring atoms are independently selected from the group consisting of N, S and O, and bicyclic heteroaryl having a phenyl ring fused to a monocyclic heteroaryl ring as defined above, optionally substituted with F, Cl, Br, I, —OH, —NH₂, —CO₂H, —CO₂—C₁-C₆ alkyl, —CN, —NO₂, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perhaloalkyl, OR₃, or C₁-C₆ perhaloalkoxy; R₃ is selected from the group consisting of H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl, monocyclic heteroaryl having 5-6 ring atoms of which 1-3 ring atoms are independently selected from the group consisting of N, S and O, and bicyclic heteroaryl having a phenyl ring fused to a monocyclic heteroaryl ring as defined above, C₇-C₁₄ aralkyl, and mono or bicyclic heteroaralkyl consisting of a C₁-C₄ alkyl having a substituent which is a mono or bicyclic heteroaryl as defined above, where the aryl or heteroaryl group is optionally substituted with one to three substituents independently selected from the group consisting of F, Cl, Br, I, CN, —NH₂, —NO₂, —OH, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perhaloalkyl, C₁-C₆ alkoxy, and C₁-C₆ perhaloalkoxy.
 19. The method of claim 18 wherein the chronic pain is diabetic peripheral neuropathy. 